title: Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function.
abstract: The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Christine
authors.initials: C
authors.lastname: Saunders
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Michael
authors.initials: M
authors.lastname: Siuta
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Sabrina D
authors.initials: SD
authors.lastname: Robertson
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Adeola R
authors.initials: AR
authors.lastname: Davis
authors.affiliation: Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sauer
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Heinrich J G
authors.initials: HJG
authors.lastname: Matthies
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gresch
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: David
authors.initials: D
authors.lastname: Airey
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX.
authors.forename: John A
authors.initials: JA
authors.lastname: Schetz
authors.affiliation: Department of Medicine Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.|Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Veenstra-Vanderweele
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.|Department of Neuroscience Program in Substance Abuse, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D007328:Insulin / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000235:genetics*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D007328:Insulin; D044402:Receptor, Serotonin, 5-HT2A; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D051058:Oncogene Protein v-akt
keywords: 5HT(1A) receptor; 5HT(2A) receptor; Akt; Cortex; Serotonin